The present invention is concerned with novel oxidized analogs of 17.beta.-N-monosubstituted carbamoyl-4-aza-5.alpha.-androstan-3-one compounds and the use of such compounds as testosterone-5.alpha.-reductase inhibitors.
It is well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, and male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethylisobutyranilide. See Neri et al., Endo., Vol. 91, No. 2 (1972). However, these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.
It more recently became known in the art that the principal mediator of androgenic activity in some target organs is 5.alpha.-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh et al., Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17.beta.-carboxylate was a testosterone-5.alpha.-reductase inhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17.beta.-carboxylic acid are both active inhibitors of testosterone-5.alpha.-reductase in vitro. They further demonstrated that topical application of either testosterone or 5.alpha.-dihydrotesterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one-17.beta.-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5.alpha.-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5.alpha.-reductase.
A number of 4-aza steroid compounds are known. See, for example, U.S. Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat. No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition U.S. Pat. No. 4,377,584 and 4,220,775 and EP Appln. No. 4949 of Rasmusson et al. describe a group of 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are useful in the treatment of hyperandrogenic conditions. Recently, a number of investigators from Merck & Co., Inc. have published regarding the biological activity of 5.alpha.-reductase inhibitors. See for example, Rasmusson et al., J. Med. Chem. 29: 2298-2315 (1986), Brooks et al., The Prostate 9: 65-75 (1986), Liang et al., Endocrinology 117, No. 2, pp. 571-579 (1985), Rasmusson et al., J. Med. Chem. 27: 1690-1701 (1984), Liang et al., J. Biol. Chem. 259, No. 2, pp. 734-739 (1984). The biological activity of 17.beta.-(N-t-butylcarbamoyl)-4-aza-androst-1-en-3-one has also been reported. However, only the Rasmusson et al. (1986) reference teaches or suggests that any of the novel oxidized analogs of 17.beta.N-(monosubstituted)carbamoyl-4-aza-5 .alpha.-androstan-3-ones of the present invention would have utility as highly potent testosterone-5.alpha.-reductase inhibitors.
In addition to being 5.alpha.-reductase inhibitors and thus useful for the treatment of benign prostatic hypertrophy, acne vulgaris, seborrhea and hirsutism, certain of the compounds of the present invention are metabolites resulting from in vivo administration of 17.beta.-(N-t-butylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one. In many cases, metabolism of active drug result in deactivation and/or excretion, however, in this case the compounds of the present invention maintain a sustained high level of bioactivity in treated animals and have prolonged half-lifes.